A novel somatostatin receptor ligand for human ACTH - and GH -secreting pituitary adenomas.

Objective: Somatostatin receptor ligands have come to play a pivotal role in the treatment of both ACTH- and GH-secreting pituitary adenomas. Clinical efficacy averages 30-50%, thus a considerable number of patients with Cushing's disease or acromegaly remain unresponsive to this therapeutic approach. HTL0030310 is a new somatostatin receptor ligand selective for subtype 5 over subtype 2, thus with a different receptor profile compared to clinical somatostatin receptor ligands.

The Neutrophil Dynamic Mass Redistribution Assay as a Medium throughput Primary Cell Screening Assay.

In a typical G protein coupled receptor drug discovery campaign, an in vitro primary functional screening assay is often established in a recombinant system overexpressing the target of interest, which offers advantages with respect to overall throughput and robustness of compound testing. Subsequently, compounds are then progressed into more physiologically relevant but lower throughput ex vivo primary cell assays and finally in vivo studies. Here we describe a dynamic mass redistribution (DMR) assay that has been developed in a format suitable to support medium throughput drug screening in primary human neutrophils.

Discovery of : A Highly Potent, Selective, and CNS Penetrant mGluR Allosteric Agonist.

The low affinity metabotropic glutamate receptor mGluR has been implicated in numerous CNS disorders; however, a paucity of potent and selective activators has hampered full delineation of the functional role and therapeutic potential of this receptor. In this work, we present the identification, optimization, and characterization of highly potent, novel mGluR agonists. Of particular interest is the chromane , a potent (EC 7 nM) allosteric agonist which demonstrates exquisite selectivity for mGluR compared to not only other mGluRs, but also a broad range of targets.

The Identification of GPR52 Agonist HTL0041178, a Potential Therapy for Schizophrenia and Related Psychiatric Disorders.

HTL0041178 (), a potent GPR52 agonist with a promising pharmacokinetic profile and exhibiting oral activity in preclinical models, has been identified. This molecule was the outcome of a judicious molecular property-based optimization approach, focusing on balancing potency against metabolic stability, solubility, permeability, and P-gp efflux.

Discovery and Characterization of Novel Antagonists of the Proinflammatory Orphan Receptor GPR84.

GPR84 is a poorly characterized, nominally orphan, proinflammatory G protein-coupled receptor that can be activated by medium chain length fatty acids. It is attracting considerable interest as a potential therapeutic target for antagonist ligands in both inflammatory bowel diseases and idiopathic pulmonary fibrosis. Successful screening of more than 300 000 compounds from a small molecule library followed by detailed analysis of some 50 drug-like hits identified 3-((5,6-bis(4-methoxyphenyl)-1,2,4-triazin-3-yl)methyl)-1-indole as a high affinity and highly selective competitive antagonist of human GPR84.

Expression profiling of the adhesion G protein-coupled receptor GPR133 (ADGRD1) in glioma subtypes.

Background: Glioma is a family of primary brain malignancies with limited treatment options and in need of novel therapies. We previously demonstrated that the adhesion G protein-coupled receptor GPR133 (ADGRD1) is necessary for tumor growth in adult glioblastoma, the most advanced malignancy within the glioma family. However, the expression pattern of GPR133 in other types of adult glioma is unknown.

Breaking hearts and taking names: A case of sarcoidosis related effusive-constrictive pericarditis.

Introduction: Pericardial involvement of sarcoidosis is a rare cause for acute heart failure, and usually occurs as a result of the development of a pericardial effusion leading to cardiac tamponade. Even rarer still, is the manifestation of constrictive pericarditis. We report a case of sarcoidosis with lung, pleural, and pericardial involvement with effusive-constrictive pericarditis leading to cardiac tamponade.

Match and Training Injuries in Women's Rugby Union: A Systematic Review of Published Studies.

Background: There is a paucity of studies reporting on women's injuries in rugby union.

Objective: The aim of this systematic review was to describe the injury epidemiology for women's rugby-15s and rugby-7s match and training environments.

Methods: Systematic searches of PubMed, SPORTDiscus, Web of Science Core Collection, Scopus, CINAHL(EBSCO) and ScienceDirect databases using keywords.

On-target and off-target effects of novel orthosteric and allosteric activators of GPR84.

Many members of the G protein-coupled receptor family, including examples with clear therapeutic potential, remain poorly characterised. This often reflects limited availability of suitable tool ligands with which to interrogate receptor function. In the case of GPR84, currently a target for the treatment of idiopathic pulmonary fibrosis, recent times have seen the description of novel orthosteric and allosteric agonists.

Identification of compounds acting as negative allosteric modulators of the LPA receptor.

The Lysophosphatidic Acid 1 Receptor (LPA receptor) has been linked to the initiation and progression of a variety of poorly treated fibrotic conditions. Several compounds that have been described as LPA receptor antagonists have progressed into clinical trials: 1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]phenyl}phenyl)cyclopropane-1-carboxylic acid (BMS-986202) and 2-{4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzamido}-2,3-dihydro-1H-indene-2-carboxylic acid (SAR-100842). We considered that as LPA receptor function is involved in many normal physiological processes, inhibition of specific signalling pathways associated with fibrosis may be therapeutically advantageous.

Enhanced insulin receptor, but not PI3K, signalling protects podocytes from ER stress.

Disruption of the insulin-PI3K-Akt signalling pathway in kidney podocytes causes endoplasmic reticulum (ER) stress, leading to podocyte apoptosis and proteinuria in diabetic nephropathy. We hypothesised that by improving insulin sensitivity we could protect podocytes from ER stress. Here we use established activating transcription factor 6 (ATF6)- and ER stress element (ERSE)-luciferase assays alongside a novel high throughput imaging-based C/EBP homologous protein (CHOP) assay to examine three models of improved insulin sensitivity.

and regulate vacuolar size and function in .

The yeast vacuole plays key roles in cellular stress responses. Here, we show that deletion of , the fission yeast homolog of the Chediak-Higashi Syndrome / gene, increases vacuolar size, similar to deletion of the Rab4 homolog . Overexpression of lvs1-YFP rescued vacuolar size in cells, but ypt4-YFP did not rescue , suggesting that may act downstream of .

Assessment of the Target Engagement and D-Serine Biomarker Profiles of the D-Amino Acid Oxidase Inhibitors Sodium Benzoate and PGM030756.

Irregular N-methyl-D-aspartate receptor (NMDAR) function is one of the main hypotheses employed to facilitate understanding of the underlying disease state of schizophrenia. Although direct agonism of the NMDAR has not yielded promising therapeutics, advances have been made by modulating the NMDAR co-agonist site which is activated by glycine and D-serine. One approach to activate the co-agonist site is to increase synaptic D-serine levels through inhibition of D-amino acid oxidase (DAO), the major catabolic clearance pathway for this and other D-amino acids.

Selective FFA2 Agonism Appears to Act via Intestinal PYY to Reduce Transit and Food Intake but Does Not Improve Glucose Tolerance in Mouse Models.

Free fatty acid receptor 2 (FFA2) is expressed on enteroendocrine L cells that release glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) when activated by short-chain fatty acids (SCFAs). Functionally GLP-1 and PYY inhibit gut transit, increase glucose tolerance, and suppress appetite; thus, FFA2 has therapeutic potential for type 2 diabetes and obesity. However, FFA2-selective agonists have not been characterized in vivo.

Immunomodulation by lipid emulsions in pulmonary inflammation: a randomized controlled trial.

Introduction: Acute respiratory distress syndrome (ARDS) is a major cause of mortality in intensive care units. As there is rising evidence about immuno-modulatory effects of lipid emulsions required for parenteral nutrition of ARDS patients, we sought to investigate whether infusion of conventional soybean oil (SO)-based or fish oil (FO)-based lipid emulsions rich in either n-6 or n-3 fatty acids, respectively, may influence subsequent pulmonary inflammation.

Methods: In a randomized controlled, single-blinded pilot study, forty-two volunteers received SO, FO, or normal saline for two days.

Identification of a novel GPR81-selective agonist that suppresses lipolysis in mice without cutaneous flushing.

GPR81, which exhibits a high degree of homology with GPR109a, has been recently identified as a lactate receptor. Similar to GPR109a, the activation of GPR81 by lactate suppresses lipolysis, suggesting that GPR81 may be a potential drug target for treating dyslipidemia. In addition, the fact that GPR81 is expressed only in adipocytes, whereas GPR109a is expressed in various tissues and cells, including Langerhans cells, which are considered responsible for flushing, indicates that targeting GPR81 could lead to the development of antidyslipidemia agents with a reduced risk of this side effect.

Multi-paddock grazing on rangelands: why the perceptual dichotomy between research results and rancher experience?

Maintaining or enhancing the productive capacity and resilience of rangeland ecosystems is critical for the continued support of people who depend on them for their livelihoods, especially in the face of climatic change. This is also necessary for the continued delivery of ecosystem services derived from rangelands for the broader benefit of societies around the world. Multi-paddock grazing management has been recommended since the mid-20th century as an important tool to adaptively manage rangelands ecosystems to sustain productivity and improve animal management.

The incidence of infection after posterior cervical spine surgery: a 10 year review.

Background The incidence of infection after posterior cervical spine surgery ranges from 0 to 18%. Higher rates have been reported after posterior procedures compared with anterior procedures, but these studies have been for small series. We report on our rate of surgical site infection (SSI) after posterior cervical spine surgery and the risk factors that influence these infections.

Efficacy and tolerability assessment of a topical formulation containing copper sulfate and hypericum perforatum on patients with herpes skin lesions: a comparative, randomized controlled trial.

Background: Topical Acyclovir has moderate efficacy on recurrent HSV symptoms, requiring repeat applications for several days. Topical Dynamiclear, which requires only a single dose application, may provide a more effective and convenient treatment option for symptomatic management of HSV.

Objectives: The study assessed the comparative efficacy and tolerability of a single use, topical formulation containing copper sulfate pentahydrate and Hypericum perforatum that is marketed as Dynamiclear™ to a topical 5% Acyclovir cream standard preparation and use.

The effects of compression garments on intermittent exercise performance and recovery on consecutive days.

Purpose: The aim of this study was to determine whether compression garments improve intermittent-sprint performance and aid performance or self-reported recovery from high-intensity efforts on consecutive days.

Methods: Following familiarization, 14 male rugby players performed two randomized testing conditions (with or without garments) involving consecutive days of a simulated team sport exercise protocol, separated by 24 h of recovery within each condition and 2 weeks between conditions. Each day involved an 80-min high-intensity exercise circuit, with exercise performance determined by repeated 20-m sprints and peak power on a cart dynamometer (single-man scrum machine).